6ira

From Proteopedia

(Difference between revisions)

Current revision

Structure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 7.8

6ira, resolution 4.50Å

Structural highlights

6ira is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.5Å
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NMDE1_HUMAN Landau-Kleffner syndrome;Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation;Continuous spikes and waves during sleep;Rolandic epilepsy;Rolandic epilepsy - speech dyspraxia. The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2). GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma.^[1] ^[2]

Function

NMDE1_HUMAN NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits.

Publication Abstract from PubMed

N-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during vesicle exocytosis by mechanisms that are unknown. We used cryo-electron microscopy to solve the structures of the human GluN1-GluN2A NMDA receptor at pH 7.8 and pH 6.3. Our structures demonstrate that the proton sensor predominantly resides in the N-terminal domain (NTD) of the GluN2A subunit and reveal the allosteric coupling mechanism between the proton sensor and the channel gate. Under high-pH conditions, the GluN2A-NTD adopts an "open-and-twisted" conformation. However, upon protonation at the lower pH, the GluN2A-NTD transits from an open- to closed-cleft conformation, causing rearrangements between the tetrameric NTDs and agonist-binding domains. The conformational mobility observed in our structures (presumably from protonation) is supported by molecular dynamics simulation. Our findings reveal the structural mechanisms by which protons allosterically inhibit human GluN1-GluN2A receptor activity.

Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors.,Zhang JB, Chang S, Xu P, Miao M, Wu H, Zhang Y, Zhang T, Wang H, Zhang J, Xie C, Song N, Luo C, Zhang X, Zhu S Cell Rep. 2018 Dec 26;25(13):3582-3590.e4. doi: 10.1016/j.celrep.2018.11.071. PMID:30590034^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15. PMID:21499247 doi:http://dx.doi.org/10.1038/ng.810
↑ D'mello SA, Flanagan JU, Green TN, Leung EY, Askarian-Amiri ME, Joseph WR, McCrystal MR, Isaacs RJ, Shaw JH, Furneaux CE, During MJ, Finlay GJ, Baguley BC, Kalev-Zylinska ML. Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival. Front Oncol. 2014 Jan 13;3:333. doi: 10.3389/fonc.2013.00333. eCollection 2014, Jan 13. PMID:24455489 doi:http://dx.doi.org/10.3389/fonc.2013.00333
↑ Zhang JB, Chang S, Xu P, Miao M, Wu H, Zhang Y, Zhang T, Wang H, Zhang J, Xie C, Song N, Luo C, Zhang X, Zhu S. Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors. Cell Rep. 2018 Dec 26;25(13):3582-3590.e4. doi: 10.1016/j.celrep.2018.11.071. PMID:30590034 doi:http://dx.doi.org/10.1016/j.celrep.2018.11.071

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ira"

@@ Line 3: / Line 3: @@
 <SX load='6ira' size='340' side='right' viewer='molstar' caption='[[6ira]], [[Resolution|resolution]] 4.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ira]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IRA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6IRA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ira]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IRA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IRA FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6irf|6irf]], [[6irg|6irg]], [[6irh|6irh]]</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.5&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRIN2A, NMDAR2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRIN1, NMDAR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ira FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ira OCA], [https://pdbe.org/6ira PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ira RCSB], [https://www.ebi.ac.uk/pdbsum/6ira PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ira ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ira FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ira OCA], [http://pdbe.org/6ira PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ira RCSB], [http://www.ebi.ac.uk/pdbsum/6ira PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ira ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN]] Landau-Kleffner syndrome;Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation;Continuous spikes and waves during sleep;Rolandic epilepsy;Rolandic epilepsy - speech dyspraxia. The disease is caused by mutations affecting the gene represented in this entry.  A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2).  GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma.<ref>PMID:21499247</ref> <ref>PMID:24455489</ref>  [[http://www.uniprot.org/uniprot/NMDZ1_HUMAN NMDZ1_HUMAN]] Defects in GRIN1 are the cause of mental retardation autosomal dominant type 8 (MRD8) [MIM:[http://omim.org/entry/614254 614254]]. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21376300</ref>
+[https://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN] Landau-Kleffner syndrome;Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation;Continuous spikes and waves during sleep;Rolandic epilepsy;Rolandic epilepsy - speech dyspraxia. The disease is caused by mutations affecting the gene represented in this entry.  A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2).  GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma.<ref>PMID:21499247</ref> <ref>PMID:24455489</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN]] NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits. [[http://www.uniprot.org/uniprot/NMDZ1_HUMAN NMDZ1_HUMAN]] NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity).
+[https://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN] NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 27: @@
 __TOC__
 </SX>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chang, S]]
+[[Category: Chang S]]
-[[Category: Zhang, J]]
+[[Category: Zhang J]]
-[[Category: Zhang, X]]
+[[Category: Zhang X]]
-[[Category: Zhu, S]]
+[[Category: Zhu S]]
-[[Category: Ionotropic glutamate receptor]]
-[[Category: Membrane protein]]
-[[Category: Nmda receptor]]
-[[Category: Synaptic protein]]

6ira

From Proteopedia

Current revision

Structure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 7.8

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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